Clinical characteristics, pathogens implicated and therapeutic outcomes of mixed infection in adult bacterial meningitis

Kaohsiung Journal of Medical Sciences (2012) 28, 531e537

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ORIGINAL ARTICLE

Clinical characteristics, pathogens implicated and therapeutic outcomes of mixed infection in adult bacterial meningitis Wan-Chen Tsai a, Shu-Fang Chen a,1, Wen-Neng Chang a, Cheng-Hsien Lu a, Yao-Chung Chuang a, Nai-Wen Tsai a, Chiung-Chih Chang a, Chun-Chih Chien b, Chi-Ren Huang a,* a

Department of Neurology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan b Diagnostic Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan Received 8 July 2011; accepted 31 October 2011 Available online 18 August 2012

KEYWORDS Adult bacterial meningitis; Anaerobic pathogens; Hydrocephalus; Mixed infection; Post-neurosurgical state

Abstract We reviewed retrospectively the data for adult patients with bacterial meningitis over a period of 10.5 years in our hospital. The clinical characteristics and laboratory data of the 21 cases (52 strains) of mixed infection were analyzed. Two hundred and fifteen cases of single pathogen adult bacterial meningitis (ABM) were also included for comparison. Postneurosurgical type of ABM was presented in 86% of the mixed infection group. Brain abscess was found in three patients. Fourteen patients survived and seven cases died. The analysis showed a statistical significance for the mixed infection group having a higher rate of nosocomially-acquired, post-neurosurgical condition, hydrocephalus, and lower level of cerebrospinal fluid white cell count, protein and lactate than the single pathogen group. Logistic regression analysis showed the independent factor of “hydrocephalus” (p Z 0.002). Presence of hydrocephalus is a significant neuroimaging feature when compared with the single pathogen group. As compared with the previous study results of mixed infection in ABM, the present study showed a change of pathogens implicated of increasing Pseudomonas spp. and Acinetobacter spp. infections, and an emergence of anaerobic pathogens. All these changes deserve special attention because of the need for an appropriate choice of empirical antibiotics and choice of culture method. Copyright ª 2012, Elsevier Taiwan LLC. All rights reserved.

* Corresponding author. Department of Neurology, Chang Gung Memorial Hospital - Kaohsiung, Kaohsiung City 833, Taiwan. E-mail address: [email protected] (C.-R. Huang). 1 Shu-Fang Chen contributed equally to the efforts of the first author (Wan-Chen Tsai). 1607-551X/$36 Copyright ª 2012, Elsevier Taiwan LLC. All rights reserved. doi:10.1016/j.kjms.2012.04.015

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Adult bacterial meningitis (ABM) is a serious infectious disease of the central nervous system (CNS) [1,2]; unlike brain abscess, it is typically a mono-microbial infection [3]. Mixed infection in bacterial meningitis has been only rarely examined in the literature [4,5]. Clinically, several factors including varying periods of time may influence the change of epidemiologic trend of ABM [1,2] and this change may influence the choice of initial empirical antibiotics, which has been known to be an important therapeutic strategy for ABM management [6,7]. Therefore, a frequent review of the epidemiologic trend of ABM is important for a better therapeutic result. In the year 2000, we reported the clinical and laboratory features of 12 cases of ABM with mixed infection (study period: 1986e1998) [4], in which a relatively high incidence of multi-antimicrobial resistant strains was noted among the pathogens implicated. In the present study, we analyzed the epidemiologic trend of mixed infection in ABM patients, collected during a study period of 10.5 years (January 2000eJune 2010), and made a comparison with our previous report [4]. We also compared the clinical and laboratory difference between those ABM patients with mixed infection and with monomicrobial infection. This comparison was not made in our previous report [4] of mixed infection in ABM.

considered to have “mixed” bacterial meningitis if
2 bacterial organisms were isolated concomitantly from the initial CSF cultures [4]. New pathogen(s) from new culture during the therapeutic course of ABM was considered as a state of “super-infection” [9]. Both the mixed infection and super-infection were included in the group of “polymicrobial infection”. In this study, the analysis of antibiotic susceptibility was based on the NCCLS/CLS standard methods. Intermediate and resistant isolates were considered non-susceptible [10]. In this study period, vancomycin plus a third or fourth generation cephalosporin were the initial empiric antibiotics used in the treatment of patients with suspected ABM in our hospital, and the antimicrobial regimen was adjusted subsequently after the culture results were available. For a comparative analysis, the clinical features of the ABM patients with mixed infection were compared with those ABM patients with single pathogen infection. The clinical data including gender, type of infection, underlying condition, clinical presentations, antibiotics susceptibility, and therapeutic outcome were analyzed by the Fisher exact test. The data for age, CSF white blood cell count, glucose level, total protein, and lactate were compared using the ManneWhitney U test. Logistic regression analysis for independent factors was also conducted. A p value < 0.05 was considered statistically significant.

Patients and methods

Results

We reviewed retrospectively the microbiological records for cerebrospinal fluid (CSF) and medical records of adult patients with bacterial meningitis admitted to our hospital over a period of 10.5 years (January 2000eJune 2010). Our hospital is a 2482-bed acute-care teaching hospital, which serves as a primary and tertiary care center. In this study, the criteria for a definite diagnosis of ABM were as follows [1,2]: (A) age
17 years old; (B) positive CSF culture in patients with clinical presentations of acute bacterial meningitis including fever, headache, altered consciousness and seizure; and (C) at least one of the following CSF parameters: (1) a leukocyte count > 0.25  109/L with predominant polymorphonuclear cells; (2) a CSF lactate concentration > 3.5 mmol/L; (3) a glucose ratio (CSF glucose/serum glucose) < 0.4 or CSF glucose concentration < 2.5 mmol/L if no simultaneous blood glucose was determined. Coagulasenegative staphylococci were considered to be pathogenic when positive cultures in
two separate CSF studies or one positive CSF culture from the tip of indwelling neurosurgical device [8]. The hospital’s Ethics Committee approved this study (IRB 99-1897C). In this study, “nosocomial” meningitis was defined as infection not present when the patient was admitted to the hospital and the clinical evidence of meningitis was observed more than 48 hours after admission. Those with clinical evidence of meningitis within 1 month after discharge from the hospital where the patient had received an invasive neurosurgical procedure were also included. Meningitis related to traumatic skull fracture, neurosurgical procedure or any causes related to skull defects was classified as the “post-neurosurgical” form. Otherwise, patients were classified as the “spontaneous” form. Patients were

During the study period, 255 ABM patients were identified. Of them, 215 patients had monomicrobial bacterial pathogen infection (123 cases with Gram-negative [G(e)] pathogen infection and 92 cases with Gram-positive [G(þ)] pathogen infection while the other 40 cases had polymicrobial infection. Among the 40 cases of polymicrobial infection, 21 cases had mixed infection from the initial CSF culture, and were thus included in this study. The other 19 superinfection cases were excluded in this study owing to the monomicrobial infection from the first CSF culture. A total of 52 bacterial strains were isolated from the 21 ABM patients with mixed infection. Table 1 lists the pathogens implicated for the 236 ABM patients including 21 cases of mixed infection and 215 cases of monomicrobial infection. Among the implicated G(e) pathogens found in ABM with monomicrobial infection, Klebsiella pneumoniae was the most common, followed by Acinetobacter spp. and Pseudomonas spp. As to the implicated G(þ) pathogens, Staphylococcus aureus was the most common, followed by coagulase-negative staphylococci, Streptococcus pneumoniae and viridians streptococci. The 52 pathogens implicated found in the 21 ABM cases with mixed infection included 40 strains of G(e) pathogens and 12 strains of G(þ) pathogens. Of the 40 strains of G(e) pathogens, seven strains belonged to anaerobic pathogens. Of the implicated G(e) pathogens, Pseudomonas spp. (7) was the most common, followed by Acinetobacter spp. (6), Escherichia coli (6), Klebsiella spp. (4), Citrobacter spp. (2), Brevundimonas diminuta (2), Elizabethkingia meningoseptica (1), Alcaligenes faecalis (1), Comamonas acidovorans (1), Shewanella putrefaciens (1), Enterobacter cloacae (1), Proteus mirabilis (1), Fusobacterium nucleatum (1), Aeromonas caviae (1), Bacteroides distaonis (1), Bacteroides

Introduction

Mixed infection in adult bacterial meningitis

533

Table 1 The bacterial pathogens implicated in the present study (2000eJune 2010, both monomicrobial and mixed infections) and in the previous study (1986e1998, mixed infection, [4]). Pathogens

Monomicrobial infection Mixed infection Previous study mixed infection

Gram negative Klebsiella spp. Klebsiella pneumoniae Klebsiella oxytoca Acinetobacter spp. Acinetobacter baumannii Acinetobacter lwoffii Acinetobacter junnii Acinetobacter sp. Pseudomonas spp. Pseudomonas aeruginosa Psuedomonas spp. Enterobacter spp. Enterobacter cloacae Enterobacter aerogenes Citrobacter Citrobacter diversus Citrobacter freundii Escherichia coli Serratia marcences Proteus mirabilis Brevundimonas diminuta Elizabethkingia meningoseptica Alcaligenes faecalis Comamonas acidovorans Shewanella putrefaciens Neisseria meningitidis Anaerobes Others Gram positive Staphylococcus spp. Staphylococcus aureus Staphylococcus epidermidis Staphylococcus haemolyticus Staphylococcus chromogenes Unclassified coagulase-negative staphylococci Streptococcus spp. Streptococcus pneumoniae Viridian streptococci Beta-streptococci Enterococcus spp. Others

123 47 47 22 19 2 1 17 11 6a 10 7 3 1 1 10 3 2

40 4 3 1 6 1 1 2 2 7 5 2 1 1 2 1 1 6 1 2 1 1 1 1

1

2 1b 7c 92 53 30 10 2 11 24 12 10 2 8 7d

25 5 4 1 2 2

3 3 6 5 1 1 1 5 1 1

1 7e 12 5 1 2

7 4 3 1

1 1 4 1 2 1f 3

1 1 2

a

Pseudomonas mendocina (2 strains), Pseudomonas stuzeri (2), Pseudomonas putida (1), and Pseudomonas sp. (1). Fusobacterium nucleatum. c Salmonella (3), unclassified glucose non fermenting group (2), Sphingomonas paucimobilis (1), and Stenotrophomonas maltophilia (1). d Listeria monocyotgenes (3), Corynebacterium (3) and micrococcus (1). e Fusobacterium nucleatum (1), Aeromonas caviae (1), Bacteroides distaonis (1), Bacteroides fragilis (1), Bacteroides uniformis (1), Provetella sp. (1), and Provetella melaninogenica (1). f group D streptococci. b

fragilis (1), Bacteroides uniformis (1), Provetella sp. (1), and Provetella melaninogenica (1). The other 12 strains of G(þ) pathogens included Staphylococcus aureus (1), Staphylococcus epidermidis (2), Staphylococcus chromogenes (1), unclassified coagulase-negative staphylococci (1), viridian streptococci (2), Streptococcus pneumoniae (1), Group B

beta-streptococci (1), and Enterococcus (3). For comparison, Table 1 also lists the pathogens implicated from our previous report of mixed infection in ABM [4]. The clinical features, underlying conditions, pathogens implicated, and antibiotics used for treatment and therapeutic outcome of the 21 ABM patients with a mixed

534 infection are shown in Tables 2 and 3. The 21 cases included were 13 men and 8 women, aged 26e79 years (median Z 59). Post-NS conditions as the preceding event were noted in 18 patients (Cases 1e10, 14e21), and 14 (Cases 2e9, 16e21) of these 18 patients underwent an insertion of ventriculoperitoneal (V-P) shunt or external ventricular drainage (EVD). Among these 21 patients, diabetes mellitus (DM) was the most common underlying medical condition, found in four patients (Cases 1, 3, 8, 9). In this study period, the major antibiotics used for the treatment included vancomycin, linezolid, ceftazidime, cefepime, meropenem, and metronidazole in these 21 cases of mixed infection. With treatment, 14 of these 21 ABM patients with mixed infection survived and 7 of them died. The comparative results between the ABM patients with mixed infection and those with monomicrobial infection are listed in Table 3, and the significant factors included the following: nosocomial infection, post-neurosurgical type, hydrocephalus, CSF white blood cell (WBC) count, CSF protein level, and CSF lactate level. Logistic regression analysis showed that the presence of hydrocephalus (p Z 0.002) was an independent factor.

Discussion In a large-scale study of ABM reported by Durand et al. [2], mixed infection is found in 2% and 7% of the patients with community-acquired and nosocomial infection, respectively. In the present study, mixed infection was found in 8.2% (21/255) of the culture-proven ABM cases. Compared with our previous study result [4], which showed an incidence of 6.5%, the present figure is higher. Of the 21 ABM patients with mixed infection, 86% (18/21) of them had a preceding post-NS condition. This figure for incidence is also higher than that (75%, 9/12) of our previous report of mixed infection in ABM [4]. Therefore, this higher incidence of mixed infection in ABM in the present study can be attributed to the increased number of post-NS state in our ABM patients, which has been noted in our recent report of changing epidemiology of ABM [1]. In addition, as shown in Table 3, the ABM patients with a mixed infection also had a significantly higher incidence of hydrocephalus and most of the patients contracted the infection nosocomially. The high incidence of hydrocephalus among the ABM patients with mixed infection can be related to the high incidence of post-NS state as the preceding condition of this group of patients. In the CSF study, when compared with the ABM patients with monomicrobial infection, ABM patients with mixed infection had a lower WBC count, lower protein and lactate concentration. It is difficult to explain the difference in CSF findings between these two groups of ABM, the reason may be related to a high percentage of patients in the post-neurosurgical state of the mixed infection group. However, this significant difference needs further large-scale study for a better delineation. Therefore, a suspicion of ABM originating from mixed infection should be kept in mind when facing an ABM patient who has a post-NS state as the preceding event; has hydrocephalus in neuroimaging study; and contracts the infection nosocomially.

W.-C. Tsai et al. Of the bacterial pathogens implicated from the present 21 ABM patients with mixed infection, G(e) pathogens were the most common (77%, 40/52), followed by G(þ) pathogens (23%, 12/52). The anaerobic pathogens accounted for 13% of the 52 pathogens. In this specific infectious syndrome, a relatively higher number of G(e) pathogen was also noted in our previous report of mixed infection in ABM [4]. In our previous study [4], Enterobacter spp., Escherichia coli and Klebsiella spp. were the common G(e) pathogens, while in the present study, Pseudomonas spp. was the most common, followed by Acinetobacter spp. and Escherichia coli. This change in relative frequency of leading G(e) pathogens is consistent with the finding of a recent report of changing epidemiology of overall ABM in Taiwan [1]. Both Acinetobacter spp. and Pseudomonas spp. are important causative pathogens of ABM patients with a post-NS state as the preceding event and those who contracted the infection nosocomially [1]. The high incidence of multi-antibiotic resistant Acinetobacter spp. and Pseudomonas spp. strains is also found in recent studies [11e13] and deserves attention because it may influence the choice of empiric antibiotics. In this study, G(þ) pathogens accounted for 24.5% (12/ 49) of the pathogens implicated of ABM with mixed infection, in which staphylococcal, streptococcal and enterococcal spp. were the common ones. This combination of implicated G(þ) pathogens was the same as in our previous report of mixed infection [4] and they are all common G(þ) pathogens of ABM in Taiwan [1,4,10,14,15] and had high incidence of antimicrobial resistance. Therefore, the choice of vancomycin or linezolid as the antimicrobial agent for their infection-related ABM was required and this antibiotic choice was also noted in this study. Compared with our previous study of mixed infection in ABM [4], the most different finding in the present study was the presence of anaerobic pathogens (Aeromonas caviae, Bacteroides spp., Fusobacterium nucleatum and Prevotella spp.) as the pathogens implicated. The lack of anaerobic strains as the pathogens implicated in the previous studies of mixed infection in bacterial meningitis [4,5] can be partially because the anaerobic culture was not a routine culture performed in clinical study. In present study, these anaerobic pathogens accounted for 13.5% (7/52) of the pathogens implicated for mixed infection in ABM. Prevotella meningitis was rarely reported and its infection was noted mostly in children or adolescents [16e18]. In the present two Prevotella infection-related ABM cases, one had an underlying post-NS condition (Case 7) and one had a co-existing brain abscess (Case 13). Aeromonas spp. is a rare anaerobic pathogen for meningitis [19,20]; in this study, Case 11 had a recent stomach operation and also had respiratory failure as the preceding conditions of its infection. CNS infections including meningitis and brain abscess can be found in fusobacterial infection [21,22]. Case 13 had a coexisting brain abscess with this fusobacterial (Fusobacterium nucleatum) infection. Bacteroid spp. is not a common pathogen of ABM [23e25] and its infection is usually seen in ABM patients with head and neck tumor or with intracranial focal suppuration. In this study, all two patients (Cases 2 and 16) had a preceding neurosurgical event as the underlying condition. Anaerobic pathogens need a longer duration (10 dayse3 months) of

Patient

The clinical data, pathogens implicated, antibiotics used and therapeutic outcome of the 21 adult bacterial meningitis patients with mixed infection. Age/Gender

Underlying condition

Pathogens

Antibiotics

Survived

1 2

57/F 40/M

DM, Infarct, craniectomy, abscess SICH, craniectomy, EVD, VPS, cranioplasty

ROC, CIP VA, CAZ, MET

No Yes

3 4

64/F 34/M

DM, RHD, SICH, craniectomy, EVD TICH, craniectomy, VPS, cranioplasty

VA, CAZ LZD

No Yes

5 6 7 8 9

63/M 50/F 26/M 77/M 67/F

SICH, craniotomy, EVD Infarct, craniectomy, EVD TICH, craniotomy, VPS DM, Hydrocephalus, VPS DM, Infarct, hydrocephalus, EVD, VPS

MEP MAX LZD VA, CAZ MEP

Yes Yes No Yes Yes

10

44/M

TICH, craniotomy, abscess

VA, CAZ

Yes

11 12 13

79/M 78/F 46/M

Perforation peptic ulcer post operation

MEP MAX VA, CAZ

Yes Yes No

14 15 16

30/M 59/M 77/F

TICH, craniectomy, cranioplasty SICH, craniotomy SICH, craniotomy, VPS

VA, MEP MEP VA, ROC, MET

Yes No Yes

17 18 19

58/F 72/M 20/M

SICH, EVD SICH, VPS TICH, EVD, VPS

VA, ROC MAX VA, MEP

Yes No No

20 21

68/M 42/F

SICH, EVD SICH, EVD

Escherichia coli, Elizabethkingia meningoseptica Enterococcus, Klebsiella oxytoca, Pseudomonas aeruginosa, Escherichia coli, Bacteroides distaonis,a Bacteroides uniformisa Escherichia coli, Enterococcus Coagulase-negative staphylococci, Staphylococcus chromogenes Citrobacter freundii, Escherichia coli Klebsiella pneumoniae, Enterobacter cloacae Staphylococcus aureus, Prevotella sp.a Staphylococcus epidermidis, Acinetobacter junnii Alcaligenes faecalis, Comamonas acidovorans, Brevundimonas diminuta Escherichia coli, Pseudomonas aeruginosa, Streptococcus pneumoniae Pseudomonas sp., Aeromonas caviae Pseudomonas sp., Acinetobacrer sp. Viridian streptococci, Fusobacterium nucleatum,a Prevotella melaninogenicaa Acinetobacter buamannii, viridian streptococci Acinetobacter spp, Brevundimonas diminuta Bacteroides fragilis, Escherichia coli, Klebisella pneumoniae, Group D streptococci Staphylococcus epidermidis, Acinetobacter lwoffii Pseudomonas aeruginosa, Citrobacter diversus Pseudomonas aeruginosa, Klebsiella pneumoniae, Proteus mirabilis Acinetobacter junnii, Enterococcus faecalis Pseudomonas aeruginosa, Shewanella putrefaciens

VA, CAZ MAX

Yes Yes

Brain abscess

Mixed infection in adult bacterial meningitis

Table 2

CAZ Z ceftazidime; CIP Z ciprofloxacin; DM Z diabetes mellitus; EVD Z external ventricular drainage; F Z female; LZD Z linezolid; M Z male; MAX Z cefepime; MEP Z meropnem; MET Z metronidazole; RHD Z rheumatic heart disease; ROC Z ceftriaxone; SICH Z spontaneous intracranial hemorrhage; TICH Z traumatic intracranial hemorrhage; VA Z vancomycin; VPS Z ventriculo-peritoneal shunt. a Cultured from anaerobic culture.

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Table 3 Clinical and laboratory comparison between the adult bacterial meningitis patients with mixed infection and monomicrobial infection. Factors

Mixed infection (n Z 21)

Monomicrobial infection (n Z 215) 56 (18e87)

p

Age (y); median (range)

59 (26e79)

Gender Male Female

13 (62%) 8 (38%)

152 (71%) 63 (29%)

0.456

Underlying condition Diabetes mellitus Liver cirrhosis Alcoholism Ear infection Drug abuser End stage renal diseases Malignancy Nosocomial-acquired Post-neurosurgical type

4 (19%) 0 0 0 0 0 0 16 (76%) 18 (86%)

58 15 15 6 6 9 27 113 130

(27%) (7%) (7%) (3%) (3%) (4%) (12%) (52%) (60%)

0.605 0.373 0.373 1.000 1.000 1.000 0.143 0.041* 0.031*

Clinical presentation Fever Altered consciousness Seizure Shock Hydrocephalus Hyperglycemia hyperosmolarity syndrome Cerebrospinal fluid leak Subdural empyema Brain abscess Liver abscess Positive blood culture Leukocytosis

18 9 5 1 14 0 1 0 3 0 2 15

182 123 56 25 72 10 10 9 21 9 56 139

(85%) (57%) (26%) (12%) ((33%) (5%) (5%) (4%) (10%) (4%) (26%) (65%)

1.000 0.252 1.000 0.484 0.004* 0.606 1.000 1.000 0.458 1.000 0.114 0.636

0.46 2.48 2.24 9.02

(0.10, (0.33, (0.95, (4.81,

(86%) (43%) (24%) (5%) (67%) (5%) (14%) (10%) (71%)

Cerebrospinal fluid study, median (IQR) (25%, 75%) White cell count (109/L) 0.06 (0.006, 0.175) Glucose (mmol/L) 3.36 (2.14, 4.65) Protein (g/L) 0.73 (0.55, 1.80) Lactate (mmol/L) 4.39 (2.39, 6.05) Cases, non-susceptible to Ceftazidime Cefepime Meropnem Prognosis Survived Expired

1.88) 4.13) 5.20) 16.50)

0.748

0.001** 0.110 0.005** 0.003**

7 (33%) 3 (14%) 3 (14%)

30 (14%) 21 (10%) 11 (5%)

0.250 1.000 0.390

14 (67%) 7 (33%)

145 (67%) 70 (33%)

1.000

* Fisher exact test (p < 0.05); ** Mann-Whitney U test (p < 0.05). IQR Z interquartile range. Logistic regression analysis showed independent factor of “hydrocephalus” (p Z 0.002).

antibiotic treatment [26,27]; therefore, the identification of these uncommon pathogen-related infections in ABM is extremely important because their infections need a different consideration of antibiotic choice as well as therapeutic course [26,27]. The antimicrobial agents such as metronidazole, carbapenems, and a combination of penicillin and beta-lactamase inhibitor are the antibiotics of choice for treating anaerobic pathogen-related CNS infections [17,27].

In conclusion, mixed infection is not an uncommon situation in ABM and its incidence is increasing. Usually this group of patients has a post-NS state as the underlying condition and contract the infection nosocomially. Presence of hydrocephalus is also a significant neuroimaging feature when compared with the ABM with monomicrobial infection. Compared with the previous report of mixed infection of ABM, the present study showed the following differences: (1) a change of the relative frequency of

Mixed infection in adult bacterial meningitis implicated G(e) pathogens; and (2) an emergence of anaerobic bacteria as the pathogens implicated. All of these changes deserve special attention because of the need for an appropriate choice of empirical antibiotics and choice of culture method.

537

[13]

[14]

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